Thyroid cancer is the most common type of endocrine neoplasia and the fastest growing cancer type in the U.S.. Importantly, only small proportion of thyroid cancers have aggressive behavior and pose a substantial risk of cancer-related death, whereas the majority of them are indolent and cured by surgical removal. This is particularly true for well-differentiated thyroid papillary and follicular cancers, that have a 5-year survival of >95%, whereas the survival decreases to 50% for poorly differentiated cancer and to <10% for anaplastic cancer. In fact, anaplastic thyroid cancer is one of the most lethal types of human cancer with the median patient survival of 5 months after diagnosis. Better understanding of the molecular mechanisms of thyroid cancer dedifferentiation and finding novel therapeutic targets for these tumors is critically needed to decrease the morbidity and mortality from thyroid cancer. Recently, we identified ALK fusions in thyroid cancer, including poorly differentiated carcinomas and anaplastic carcinomas. We further showed that STRN-ALK fusion type is the most common ALK fusion found in thyroid cancer, and it is also most prevalent ALK fusion type found in dedifferentiated and lethal thyroid cancers. Moreover, during the previous cycle of the proposal, we established two animal models of thyroid-specific expression of STRN-ALK and showed that these mice develop dedifferentiated thyroid cancer that recapitulates human tumors. We also generated data pointing to the existence of two subtypes of poorly differentiated thyroid cancer with distinct expression of thyroid differentiation markers and response to radioiodine therapy. Importantly, ALK rearrangements that occur in other cancer types are an excellent therapeutic target, with several ALK inhibitors developed and approved by the FDA for treatment of ALK-positive lung cancer. However, whether ALK inhibitors can be used to treat ALK-positive thyroid poorly differentiated and anaplastic cancers or improve the effects of treatment of these tumors with radioactive iodine remain unknown. In the current proposal, we will take advantage of the abundant preliminary data and existing and newly generated mouse models to better understand the molecular mechanisms of thyroid cancer dedifferentiation, examine the response of STRN-ALK-positive tumors to ALK inhibitors, and determine if ALK inhibition can be exploited to restore iodine uptake and increase sensitivity to radioiodine at different stages of thyroid cancer dedifferentiation. These experiments will also provide an opportunity to test the growing list of available ALK inhibitors and hopefully validate for the first time an effective treatment for the devastating and frequently lethal forms of thyroid cancer.